Locus Reference Genomic sequences: an improved basis for describing human DNA variants

As our knowledge of the complexity of gene architecture grows, and we increase our understanding of the subtleties of gene expression, the process of accurately describing disease-causing gene variants has become increasingly problematic. In part, this is due to current reference DNA sequence formats that do not fully meet present needs. Here we present the Locus Reference Genomic (LRG) sequence format, which has been designed for the specific purpose of gene variant reporting. The format builds on the successful National Center for Biotechnology Information (NCBI) RefSeqGene project and provides a single-file record containing a uniquely stable reference DNA sequence along with all relevant transcript and protein sequences essential to the description of gene variants. In principle, LRGs can be created for any organism, not just human. In addition, we recognize the need to respect legacy numbering systems for exons and amino acids and the LRG format takes account of these. We hope that widespread adoption of LRGs - which will be created and maintained by the NCBI and the European Bioinformatics Institute (EBI) - along with consistent use of the Human Genome Variation Society (HGVS)-approved variant nomenclature will reduce errors in the reporting of variants in the literature and improve communication about variants affecting human health. Further information can be found on the LRG web site: http://www.lrg-sequence.org

Posture of the arm when grasping spheres to place them elsewhere

Despite the infinitely many ways to grasp a spherical object, regularities have been observed in the posture of the arm and the grasp orientation. In the present study, we set out to determine the factors that predict the grasp orientation and the final joint angles of reach-tograsp movements. Subjects made reach-to-grasp movements toward a sphere to pick it up and place it at an indicated location. We varied the position of the sphere and the starting and placing positions. Multiple regression analysis showed that the sphere's azimuth from the subject was the best predictor of grasp orientation, although there were also smaller but reliable contributions of distance, starting position, and perhaps even placing position. The sphere's initial distance from the subject was the best predictor of the final elbow angle and shoulder elevation. A combination of the sphere's azimuth and distance from the subject was required to predict shoulder angle, trunkhead rotation, and lateral head position. The starting position best predicted the final wrist angle and sagittal head position. We conclude that the final posture of the arm when grasping a sphere to place it elsewhere is determined to a larger extend by the initial position of the object than by effects of starting and placing position. © 2010 Springer-Verlag

Knowledge brokering: Exploring the process of transferring knowledge into action

There are many theories about knowledge transfer but there are few clear descriptions of knowledge transfer interventions or the processes they involve. This failure to characterise structure and process in proposed KT interventions is a major barrier to the design and implementation of evaluations of particular KT strategies. This study is designed to provide a detailed description of the processes involved in a knowledge transfer intervention and to develop and refine a useful model of the knowledge transfer process

Lamin A/C truncation in dilated cardiomyopathy with conduction disease

BACKGROUND: Mutations in the gene encoding the nuclear membrane protein lamin A/C have been associated with at least 7 distinct diseases including autosomal dominant dilated cardiomyopathy with conduction system disease, autosomal dominant and recessive Emery Dreifuss Muscular Dystrophy, limb girdle muscular dystrophy type 1B, autosomal recessive type 2 Charcot Marie Tooth, mandibuloacral dysplasia, familial partial lipodystrophy and Hutchinson-Gilford progeria. METHODS: We used mutation detection to evaluate the lamin A/C gene in a 45 year-old woman with familial dilated cardiomyopathy and conduction system disease whose family has been well characterized for this phenotype [1]. RESULTS: DNA from the proband was analyzed, and a novel 2 base-pair deletion c.908_909delCT in LMNA was identified. CONCLUSIONS: Mutations in the gene encoding lamin A/C can lead to significant cardiac conduction system disease that can be successfully treated with pacemakers and/or defibrillators. Genetic screening can help assess risk for arrhythmia and need for device implantation

UK-68,798, A Class III Antiarrhythmic Drug with Antifibrillatory Properties

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74787/1/j.1527-3466.1992.tb00244.x.pd

Identification of a Novel Signaling Pathway and Its Relevance for GluA1 Recycling

We previously showed that the serum- and glucocorticoid-inducible kinase 3 (SGK3) increases the AMPA-type glutamate receptor GluA1 protein in the plasma membrane. The activation of AMPA receptors by NMDA-type glutamate receptors eventually leads to postsynaptic neuronal plasticity. Here, we show that SGK3 mRNA is upregulated in the hippocampus of new-born wild type Wistar rats after NMDA receptor activation. We further demonstrate in the Xenopus oocyte expression system that delivery of GluA1 protein to the plasma membrane depends on the small GTPase RAB11. This RAB-dependent GluA1 trafficking requires phosphorylation and activation of phosphoinositol-3-phosphate-5-kinase (PIKfyve) and the generation of PI(3,5)P2. In line with this mechanism we could show PIKfyve mRNA expression in the hippocampus of wild type C57/BL6 mice and phosphorylation of PIKfyve by SGK3. Incubation of hippocampal slices with the PIKfyve inhibitor YM201636 revealed reduced CA1 basal synaptic activity. Furthermore, treatment of primary hippocampal neurons with YM201636 altered the GluA1 expression pattern towards reduced synaptic expression of GluA1. Our findings demonstrate for the first time an involvement of PIKfyve and PI(3,5)P2 in NMDA receptor-triggered synaptic GluA1 trafficking. This new regulatory pathway of GluA1 may contribute to synaptic plasticity and memory

Antiarrhythmic and antioxidant activity of novel pyrrolidin-2-one derivatives with adrenolytic properties

A series of novel pyrrolidin-2-one derivatives (17 compounds) with adrenolytic properties was evaluated for antiarrhythmic, electrocardiographic and antioxidant activity. Some of them displayed antiarrhythmic activity in barium chloride-induced arrhythmia and in the rat coronary artery ligation-reperfusion model, and slightly decreased the heart rate, prolonged P–Q, Q–T intervals and QRS complex. Among them, compound EP-40 (1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one showed excellent antiarrhythmic activity. This compound had significantly antioxidant effect, too. The present results suggest that the antiarrhythmic effect of compound EP-40 is related to their adrenolytic and antioxidant properties. A biological activity prediction using the PASS software shows that compound EP-35 and EP-40 can be characterized by antiischemic activity; whereas, compound EP-68, EP-70, EP-71 could be good tachycardia agents

Intensive disc-reverberation mapping of Fairall 9: 1st year of Swift & LCO monitoring

We present results of time-series analysis of the first year of the Fairall 9 intensive disc-reverberation campaign. We used Swift and the Las Cumbres Observatory global telescope network to continuously monitor Fairall 9 from X-rays to near-infrared at a daily to sub-daily cadence. The cross-correlation function between bands provides evidence for a lag spectrum consistent with the $\tau\propto\lambda^{4/3}$ scaling expected for an optically thick, geometrically thin blackbody accretion disc. Decomposing the flux into constant and variable components, the variable component's spectral energy distribution is slightly steeper than the standard accretion disc prediction. We find evidence at the Balmer edge in both the lag and flux spectra for an additional bound-free continuum contribution that may arise from reprocessing in the broad-line region. The inferred driving light curve suggests two distinct components, a rapidly variable ($100$ days) component with an opposite lag to the reverberation signal

The influence of allogenic blood transfusion in patients having free-flap primary surgery for oral and oropharyngeal squamous cell carcinoma

The influence of perioperative blood transfusion in oral and oropharyngeal squamous cell carcinoma remains uncertain. It is believed that blood transfusion downregulates the immune system and may have an influence on cancer recurrence and survival. In all, 559 consecutive patients undergoing primary surgery for oral and oropharyngeal squamous cell carcinoma between 1992 and 2002 were included in this study. Known prognostic variables along with transfusion details were obtained from head and neck cancer and blood transfusion service databases, respectively. Adjusting for relevant prognostic factors in Cox regression, the hazard ratio for patients having 3 or more transfused units relative to those not transfused was 1.52 (95% confidence interval (CI) 0.93–2.47) for disease-specific and 1.52 (95% CI 1.05–2.22) for overall mortality. Blood transfusion of 3 or more units might confer a worse prognosis in patients undergoing primary surgery for oral and oropharyngeal squamous cell carcinoma. Therefore, every effort should be made to limit the amount of blood transfused to the minimum requirement